Crimping method

ABSTRACT

A method for crimping a stent with a PC polymer coating in a humid environment is disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 14/702,525,filed on May 1, 2015 now U.S. Pat. No. 9,375,334 B2, which is acontinuation of application Ser. No. 14/268,834, filed May 2, 2014, nowU.S. Pat. No. 9,044,312, which is a continuation of application Ser. No.13/197,611, filed Aug. 3, 2011, now U.S. Pat. No. 8,739,379, which is adivisional of application Ser. No. 12/692,536, filed Jan. 22, 2010, nowU.S. Pat. No. 8,015,684, which is a divisional of application Ser. No.11/801,955, filed May 11, 2007, now U.S. Pat. No. 7,673,379. Thepriority applications are incorporated herein by reference in theirentirety.

FIELD

This invention is directed to a process for crimping polymeric coatedstents on balloon catheters. More particularly, the invention isdirected at the use of humidity or a plasticizing agent during thecrimping process. The invention is also directed to novel crimpingdevices capable of performing the methods of the present invention.

BACKGROUND

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A surgeon introduces a catheter assembly havinga balloon portion percutaneously into the cardiovascular system of apatient via the brachial or femoral artery. The surgeon advances thecatheter assembly through the coronary vasculature until the balloonportion crosses the occlusive lesion. Once in position, the surgeoninflates the balloon to radially compress the atherosclerotic plaque ofthe lesion and remodel the vessel wall. The surgeon then deflates theballoon to remove the catheter.

An advance on PTCA involved using an intravascular stent. Mechanically,stents act as scaffoldings, physically holding open and, if desired,expanding the vessel wall. Typically, stents compress for insertionthrough small vessels and then expand to a larger diameter once inposition. U.S. Pat. No. 4,733,665, issued to Palmaz; U.S. Pat. No.4,800,882, issued to Gianturco; and U.S. Pat. No. 4,886,062, issued toWiktor disclose examples of PTCA stents. One example of a stent 2 whichincludes struts 4 is illustrated in FIG. 1. Stents have tubular bodieswith a variety of unique strut patterns and strut geometricalconfigurations, sometimes with spacing or gaps between the struts.

Stents can radially self-expand off of the delivery implement on whichthey are positioned, or crimped, or can expand by the application of aforce by the delivery implement on which the stents are crimped. Stentcrimping is a critical step in manufacturing this equipment in thatstent retention during delivery and implantation depends on it.Generally, stent crimping is the act of affixing the stent to thedelivery catheter or delivery balloon so that it remains secured,positioned or affixed to the catheter or balloon until the physiciandesires to deliver the stent at the treatment site. Good stent retentionis critical to a safe stent implantation procedure. With earliergeneration stent systems, stents could become dislodged or fall off thesystem within the patient's vasculature during delivery. In otherinstances, the stent delivery system were not able to reach the targetedlesion. When this occurs, the delivery system is withdrawn back into theguiding catheter, and the entire system withdrawn from the patient. Ithas happened that the stent is stripped off of the catheter when it iswithdrawn into the guiding catheter. This is particularly hazardous asit places the loose stent in the coronary ostium where any complicationcould affect that entire coronary artery. In order to meet thesimultaneous requirements of low profile, and good stent retention withno damage to the balloon, current stent crimping technology issophisticated. A short time ago, one process used a roll crimper. Thisdamaged many polymer coatings due to its inherent shearing action. Nextcame the collet crimper; in it, metal jaws are mounted into what isessentially a drill chuck. The jaws move in a purely radial direction.This movement was not expected to shear the coating, because it appliedforces only normal to the stent surface. But some stent geometriesrequire that stent struts scissor together during crimping. In thosegeometries, even if the crimper imposes only normal forces, the scissoraction of the stent struts imparts shear. Finally, the iris orsliding-wedge crimper was developed which imparts mostly normal forceswith some amount of tangential shear.

To use a roll crimper, first the stent is slid loosely onto the balloonportion of the catheter. This assembly is placed between the plates ofthe roll crimper. With an automated roll crimper, the plates cometogether and apply a specified amount of force. They then move back andforth a set distance in a direction that is perpendicular to thecatheter. The catheter rolls back and forth under this motion, and thediameter of the stent is reduced. The process can be broken down intomore than one step, each with its own level of force, translationaldistance, and number of cycles. With regard to a polymer stent or drugdelivery coated stent, this process imparts a great deal of shear to thestent in a direction perpendicular to the catheter or catheter wall.Furthermore, as the stent is crimped, there is additional relativemotion between the stent surface and the crimping plates. As a result,this crimping process tends to damage the stent or the coating.

The collet crimper is equally conceptually simple. A standarddrill-chuck collet is equipped with several pie-piece-shaped jaws. Thesejaws move in a radial direction as an outer ring is turned. To use thiscrimper, a stent is loosely placed onto the balloon portion of acatheter and inserted in the center space between the jaws. Turning theouter ring causes the jaws to move inward. An issue with this device isdetermining or designing the crimping endpoint. One scheme is toengineer the jaws so that when they completely close, they touch and acenter hole of a known diameter remains. Using this approach, turningthe collet onto the collet stops crimps the stent to the known outerdiameter. While this seems ideal, it can lead to problems. Stent strutshave a tolerance on their thickness. Additionally, the process offolding non-compliant balloons is not exactly reproducible.Consequently, the collet crimper exerts a different amount of force oneach stent in order to achieve the same final dimension. Unless thisforce, and the final crimped diameter, is carefully chosen, thevariability of the stent and balloon dimensions can yield stent,coating, or balloon damage.

Furthermore, although the collet jaws move in a radial direction, theymove closer together as they crimp. This action, combined with thescissoring motion of the struts, imparts tangential shear on a polymerstent or a coating that can also lead to damage. Lastly, the actualcontact surfaces of the collet crimper are the jaw tips. These surfacesare quite small, and only form a cylindrical surface at the final pointof crimping. Before that point, the load being applied to the stentsurface is discontinuous.

In the sliding wedge or iris crimper, adjacent pie-piece-shaped sectionsmove inward and twist, much like the leaves in a camera aperture. Thiscrimper can be engineered to have two different types of endpoints. Itcan stop at a final diameter, or it can apply a fixed force and allowthe final diameter to float. From the discussion on the collet crimper,there are advantages in applying a fixed level of force as variabilitiesin strut and balloon dimension will not change the crimping force. Thesliding wedges impart primarily normal forces, which are the leastdamaging to stent coatings. As the wedges slide over each other, theyimpart some tangential force. But the shear damage is frequently equalto or less than that of the collet crimper. Lastly, the sliding wedgecrimper presents a nearly cylindrical inner surface to the stent, evenas it crimps. This means the crimping loads are distributed over theentire outer surface of the stent.

All current stent crimping methods were developed for all-metal stents.Stent metals, such as stainless steel, are durable and can take abuse.When crimping was too severe, it usually damaged the underlying balloon,not the stent. But polymeric stents and polymeric coatings presentdifferent challenges.

Moreover, as part of polymeric stent manufacture, brittle polymericmaterial is laser cut. The polymer's brittle nature and the stressinduced by laser cutting can cause stress cracking in the polymericstent during the crimping process.

In the drug eluting or delivery stent arena, drugs are commonly placedor coated on the stent in combination with a polymer, or mixed into thepolymer body for polymeric stents. This placement typically coats allstent surfaces or causes the drug to be distributed throughout thepolymeric stent. Then the stent is crimped onto the catheter. Ingeneral, polymer coatings are softer, weaker, and less durable than theunderlying stent material. Upon crimping, for example with a slidingwedge crimper, and following crimp protocols for the particular stent,coating damage is frequently seen. For polymers that are brittle orhard, crimping process can crack the stent coating or the polymericstent strut.

Grip is a process conducted after crimping to further increase stentretention. An outer sleeve restrains the crimped stent. Simultaneously,pressure and heat are applied to the stent-balloon section. Under thisaction, the balloon material deforms slightly, moving in between thestruts. In a wet expansion test, the final stent-on-catheter assembly isimmersed in deionized water at 37° C. for 30 seconds. Then the balloonis inflated according to the device instructions to at least a nominalpressure (e.g., 8 atmospheres). After holding this pressure for 30seconds, the balloon is deflated, and the stent slides off. Afterdrying, the stent can be examined by optical microscopy or scanningelectron microscopy for coating damage.

The primary purpose of the polymer in the stent coating is to containthe drug and control its release at a desired rate. Other obviousspecifications for the polymer are a high level of vascularbiocompatibility and the ability to flex and elongate to accommodatestent expansion without cracking or peeling. Meeting all of theseobjectives, while also possessing a high level of toughness and strengthto withstand conventional crimping process, can be challenging.

A crimping device and process that minimizes damage to the polymercoatings of stents is needed. Moreover, a crimping process thatminimizes internal stress or strain in the polymeric substrate of apolymeric stent is also needed.

SUMMARY

The current invention is related to devices and methods for makingmedical devices such as implantable medical devices, including stents.These medical devices can comprise portions with coatings. In someembodiments, the coating comprises a polymer, polymer combination,drug(s), or combination of polymer(s) and drug(s). In some embodiments,the device itself can be made in full or in part from a polymer orpolymer combination. The piece comprising the coating or made from thepolymer is crimped onto another part of the medical device or onto aseparate medical device, such as a delivery device or a balloon of acatheter assembly. In some embodiments, crimping is done at a high andcontrolled humidity. The stent, with or without a coating, can beexposed to humidity immediately followed by the crimping process. Thestent or coating can be exposed to humidity and the humidity maintainedat least partially during the crimping process or throughout theduration of the crimping process. In some embodiments, the stent orcoating can be exposed to the humidity during the crimping process andif desired the humidity can be maintained or a level of humidity canlast during at least a part of the crimping process. In someembodiments, the relative humidity can be adjusted during the crimpingprocess. In some embodiments, high humidity should exist at least untilthe stent is considered crimped and compressed on the balloon such asfor example when the crimping apparatus has closed on the stent (e.g.,crimping jaws or rollers have reduced the diameter of the stent to thedesired crimped diameter). High humidity can exist or alternatively canbe terminated when the crimping apparatus opens back up after securingthe stent on the balloon, such as when crimping jaws or rollers arereleased and retracted off the stent. High humidity can be defined as atleast 20% to 100% relative humidity at temperature of 25° C. In someembodiments, the relative humidity (at 25° C.) can be at least 25%, 30%,35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% orany range between any of these disclosed percentages (e.g., 20% to 60%;30% to 35%; 50% to 95%, etc.). Following the crimping process, moisturecan be allowed to evaporate or can be removed by force, such as byexposure to high temperatures or blowing gas, such as an inert gas, ontothe stent. The gas can be at an elevated temperature.

In some embodiments, the stent or coating can be exposed to aplasticizing agent such as a plasticizing solvent or fluid followed bythe crimping process. The plasticizing agent should remain on or havemigrated within the stent body or coating for the crimping process. Insome embodiments, the agent can be introduced to the stent or thecoating during the crimping process and should remain on or within thestent or coating during at least a part of the crimping process orduring the entire duration of the crimping process.

In accordance with another aspect of the invention, a stent crimpingdevice is provided that includes a crimping chamber or section in whichthe stent can be positioned and a component for introducing water vapor,moisture (purified water or buffered saline solution), or a plasticizingagent into the crimping chamber or section.

In some embodiments, the temperature of the plasticizing fluid orsolvent should be at non-ambient temperatures.

The methods and devices of the present invention can be used on avariety of polymeric materials including those characterized as having aglass transition temperature (Tg) above ambient temperature. Preferably,the polymer has a Tg, in a dry state, prior to exposure to humidity,above: 30° C., 40° C., 50° C., 60° C., 70° C., and 80° C. Morepreferably, the polymer can have a dry state Tg above 90° C.

In some embodiments, the devices and methods of the present inventionare preferably used with polymers having greater than a 60 shore Dhardness. In some embodiments, shore D hardness of the polymer can begreater than 65, 70, 75, 80, 85, 90, and 95.

Some embodiments operate on drug-containing pieces. In some of theseembodiments, the drugs are selected from the following types:antiproliferative, antineoplastic, antiinflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,antioxidants, or their combinations.

In some embodiments, high humidity is selected from a group thatspecifically excludes any one or any combination of the humidity rangesdescribed herein. In some embodiments, the selection of the relativehumidity is based on minimizing stent or coating damage, includingcracking of the polymer, as well as deformation- and delamination-basedfailure during crimping.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows a conventional stent.

FIG. 2 shows a crimping apparatus in accordance with one embodiment ofthe present invention.

DETAILED DESCRIPTION

The current invention is related to devices and method of making medicaldevices such as implantable medical devices, including stents. A stentcan be self-expandable or balloon expandable. The stent can be astent-graft. These devices can comprise portions with coatings or can befully coated. In some embodiments, the coating comprises a polymer,polymer combination, drug(s), or combination of polymer(s) and drug(s).The coating can be of a single layer construct or multiple layers. Thecoating can be deposited over a metallic substrate. Coatings can beproduced by dissolving a polymer and optionally a drug in a solvent, andapplying (e.g., spraying) this composition to the stent. Once thesolvent is removed, a polymeric coating with or without a drug canremain on the stent. In some embodiments, the device itself can be madein full or in part from a polymer or polymer combination. For example,the device can be a bioabsorbable polymeric stent, with or without acoating. In other words, the struts of the stent which can function touphold luminal patentcy can be made from a bioabsorbable polymer. Acoated or coat-less piece is crimped onto another part of the device oronto a separate medical device, such as a delivery device or a balloonof a catheter assembly. Preferably, the medical device is a polymericstent, a metallic stent having a polymeric coating, or a polymeric stenthaving a polymeric coating that is crimped on a balloon of a catheterassembly.

In some embodiments, crimping is done at a high and controlled humidity.Crimping is defined as the process of compressing, securing, collapsing,loading or mounting the medical device, e.g., stent, on a deliverysystem, e.g., balloon of a catheter such that the stent has no to littlerelative movement with respect to the balloon during the deliveryprocess and is fixedly carried by the balloon until purposefuldisengaged from the balloon upon inflation of the balloon by a medicaloperator. The crimper can include jaws, rollers, belts, sliding plates,bladders or similar actuating mechanisms for performing the crimpingfunction. The crimping process generally includes the steps of insertingthe stent into a crimping apparatus followed by crimper engagement withthe stent. The engagement includes application of pressure or force tothe stent until the stent is reduced to a designated diameter. The forceapplied can be uniform or vary through the reduction of stent diameter.The force can also vary along the length of the stent. The force can bemaintained for duration of time (e.g., seconds to minutes) until thestent is adequately crimped on the balloon. The crimping device then isdisengaged from the stent and the stent can be removed from theapparatus. Examples of crimping device used in the art include thosedisclosed by U.S. Pat. Nos. 6,968,607; 6,925,847; 6,920,674; 6,108,886;6,092,273; 6,082,990; 6,074,381; 6,063,102; 6,769,161; 6,726,713; and6,640,412. The crimping can be performed in a closed chamber forcreation and maintenance of the humidity. In some embodiments, asillustrated in FIG. 2, the crimping device can include a receivingchamber, in which the stent is disposed, for allowed the stent to beexposed to high relative humidity.

Referring to FIG. 2, an embodiment of a crimping is illustrated having awork space or chamber 12 for receiving a stent 2 positioned over aballoon of a catheter 14. The stent 2 is positioned on the balloon andfeed into the work space 12. The work spaces closes, applying a force tothe stent 2, reducing the stent diameter, and crimping the stent 2 onthe balloon. The crimping apparatus 10 has been modified to include aninlet 16. The inlet 16 allows the work space 12 to be in fluidcommunication with a humidity source 18 to expose the stent to vapor ormoisture including purified water or buffered saline solution.

The coat-less stent or coated stent can be exposed to humidity followedimmediately by introducing the stent into a crimping apparatus. In onlywords, the stent is first disposed within a humidity chamber for 5minutes to 24 hours, for example. The stent is then removed from thehumidity chamber and immediately placed within the crimping device. Insome embodiments, the crimping can be conducted in the humidity chamberafter the stent has been exposed to a high relative humidity for aselected period of time. The stent or coating can be exposed to humidityand the humidity maintained at least partially during the crimpingprocess or throughout the duration of the crimping process. It ispreferably that the humidity be maintained at least until the crimpingdevice compresses the stent onto the balloon. Maintaining the relativehumidity can be defined as +/−1%, +/−2%, +/−5% or +/−10% deviation.

As for the device of FIG. 2, for example, the stent 2 is introduced intothe workspace 12 and subjected to high humidity for duration of time.Moisture or water vapor is introduced into the work space 12 via theinlet or conduit 16 from the humidity source 18. Once the coat-lessstent or coating of the stent has absorbed a sufficient amount ofmoisture, the work-space encloses on the stent, crimping the stent onthe balloon. The application of humidity can be until the crimpingdevice has engaged the stent. Alternatively, the application of humiditycan be terminated anytime during the engagement of the crimper with thestent or until termination of the engagement with the stent. Yet,alternatively, application of humidity can continue for sometime pastthe disengagement of the crimper with the stent. Such time frames forapplication of humidity are applicable to all embodiments of the presentinvention.

In some embodiments, the coat-less stent or coated stent can be exposedto the humidity during the crimping process and if desired the humiditycan be maintained during at least a part of the crimping process. Insome embodiments, the relative humidity can be adjusted during thecrimping process, either increased or decreased. For example, the amountof water vapor or moisture introduced into the workspace 12 can bereduced as the workspace 12 encloses on the stent. Reduction can beincremental or in a step-wise fashion. In some embodiments, highhumidity should exist at least until the stent is considered crimped andcompressed on the balloon (e.g., crimping jaws or rollers have reducedthe diameter of the stent to the desired crimped diameter).

In some embodiments humidified gas or air can be applied such as throughinlet 16 such that the temperature of the applied air or gas may bedifferent from ambient temperature or the clean room temperature. Insome embodiments the temperature can be above 25 deg. C. The upper limitcan be below 300 deg. C., 200 deg. C. or alternatively below 100 deg. C.In some embodiments, the temperature can be the same as ambient or evenbelow ambient.

High humidity can exist or the desired level of high humidity can bemaintained while the crimping apparatus opens back up after securing thestent on the balloon such as when crimping jaws or rollers are releasedand retracted off the stent.

High humidity can be defined as higher than ambient humidity or humidityin the clean room where the stent crimping process is performed. In someembodiments, high humidity is least 20% to 100% relative humidity attemperature of 25° C. In some embodiments, the relative humidity (at 25°C. or at the temperature of the clean room in which the procedure inconducted) can be at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, 100% or any range between any of thesedisclosed percentages (e.g., 20% to 60%; 30% to 35%; 50% to 95%, etc.).

Following the crimping process, moisture can be allowed to evaporate orcan be removed by force, such as exposure to high temperatures orblowing a gas, such as inert gas, on the stent. The gas can be at anelevated temperature. The selection of the relative humidity can bebased on minimizing stent or coating damage, including cracking of thepolymer, as well as deformation- and delamination-based failure duringcrimping.

In some embodiments, the high humidity should cause the coat-less stentor the stent coating to absorb greater than 0 (e.g., 0.1) and less than40% by weight moisture. It is preferable for the stent or coating toabsorb greater than 0 and less than 40% by weight moisture prior to theapplication of force to the stent by the crimper. This moisture levelshould be maintained during the crimping process or at least until thepoint where the crimper disengages from the stent. In some embodiments,this moisture level can be carried out sometime past the release of thestent by the crimper. In some embodiments, the moisture level can be 10%to 30% by weight, more narrowly 15% to 25% by weight. The moisture levelcan also be adjusted, either increased or decreased during the crimpingprocess. For example, as the crimper is applying pressure on the stent,the moisture level can be deceased incrementally by application of heat.

In some embodiments, the high humidity should cause the Tg of thepolymer component of the stent to decrease. The Tg can decrease by morethe 1%, 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60% or alternatively 70%.In some embodiments, it should not be reduced by more than 90%, 80%,70%, 60%, 50%, 40%, 30%, 25%, 20%, 10%, or 5%. In some embodiments, theTg of the polymeric component is reduced between 10% and 90%, between20% and 80%, between 30% and 70%, or alternatively between 40% and 60%.Preferably, the Tg is reduced between 5% to 50% or 10% to 50%. Alltemperature values are measured in Celsius.

In lieu of, or in addition to, the humidity treatment, the polymericcomponent of the stent can be exposed to a plasticizing agent prior tointroducing the stent into the crimping apparatus. The plasticizingagent can be added to the polymeric component in a dry state. Forexample, the plasticizing agent can be added to a coating that has lessthan 2% by weight or more narrowly less than 1% by weight residualsolvent that was used to manufacture the coating. In some embodiments,the coating should have less than 0.1% residual coating solvent orshould be completely (0% by weight) solvent free when the plasticizingagent is applied. The plasticizing agent can reduce the glass transitiontemperature of the polymer at the same levels described above. Theplasticizing agent can be a gas, fluid, a solvent, or a liquid or gascarrier including the agent. In some embodiment, the plasticizing agentcan be a gaseous element or compound. The exposure can be by sprayingthe stent or immersing the stent in a liquid agent or a liquid carryingthe agent. At least a majority (>50% of what was applied) of the agentshould remain on or have migrated within the stent body or coatingduring at least a part of the crimping process or during the entireduration of the crimping process. Preferably, at least a majority of thefluid or solvent should remain up to the point where the crimper startsengaging the stent.

In some embodiments, the plasticizing agent can be introduced to thestent or the coating prior to and/or during the crimping process andshould remain on or within the stent or coating during at least a partof the crimping process or during the entire duration of the crimpingprocess. For example, referring to FIG. 2, a plasticizing agent can beintroduced into the inlet 16 for contacting the stent 2 in the workspace12.

Subsequent to the crimping process, the moisture or plasticizing agentcan be removed from the stent body or the coating on the stent. Theremoval can be by evaporation at room temperature or can be induced byheating. The stent can be placed in a regular oven or convection oven.Alternatively, a heated air or gas, such as an inert gas, can bedirected at the stent. Preferably, the gas can be argon or nitrogen. Theheating can commence as soon as the crimping device initiatesdisengagement from the stent. For example, heated gas having atemperature between 30° C. to 200° C. can be forced into inlet 16.

In accordance with another aspect of the invention, a stent crimpingdevice is provided that includes a crimping chamber, workspace orsection in which the stent can be positioned. The crimper can include aninlet for allowing humidity (water, water vapor or moisture, bufferedsaline solution, etc), or a plasticizing agent (liquid agent, liquidcarrier including the agent, plasticizing gas) into the crimpingworkspace.

In some embodiments, the temperature of the plasticizing agent whenexposed to the stent can be at non-ambient temperatures, such at between30° C. to 100° C.

The methods and devices of the present invention can be used on avariety of polymeric materials including those characterized as having aTg above ambient temperature. Preferably, the polymer has a Tg in a drystate, prior to exposure to the humidity, above: 30° C., 40° C., 50° C.,60° C., 70° C., and 80° C. More preferably, the methods and devices ofthe invention are used with polymers having a dry state Tg above 90° C.

In some embodiments, the devices and methods of the present inventionare preferably used with polymers having a hardness greater than 60shore D (in a dry state or prior to treatment). In some embodiments, theshore D hardness of the polymer can be greater than 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, and 95 (in dry state or prior to treatment). Theembodiments of the present invention can be used to yield at least 50%decrease in shore hardness, alternatively, at least 40%, 30%, 25%, 20%,15%, 10%, 5%, or 1% decrease in shore D hardness. In some embodiments,the shore D hardness should not be decreased by more than 90%, 80%, 70%,60%, 50%, 40%, 30%, 25%, 20%, 10% or 5%. In some embodiments, it can bedecreased 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%,10% to 40%, 10% to 30%, 10% to 20%, 20% to 80%, 20% to 70%, 20% to 60%,20% to 50%, 20% to 40%, or 20% to 30%.

Examples of plasticizing agents include solvents such as methanol,ethanol, isopropanol, n-propanol, n-butanol, acetone, 2-butanone,diethyl ether, tetrahydrofuran, dioxane acetonitrile, dimethylformamide, dimethyl acetamide, dimethyl sulfoxide, 1-methoxy-2-propanol,methyl acetate, ethyl acetate, n-butyl acetate, methylene chloride,chloroform, toluene, pentane, hexane, cyclohexane, liquid freons, andany combination thereof.

Gaseous plasticizing agents include gaseous freons, gasousfluorocarbons, gaseous fluorohydrocarbons, gaseous chlorofluorocarbons,gaseous chlorofluorocarbons, gaseous chlorocarbons, perfluoromethane,difluoromethane, chloromethane, methane, ethane, propane, butane, carbondioxide, nitrous oxide, argon, neon, hydrogen sulfide, carbon monoxide,sulfur hexafluoride and any combination thereof.

Conventional plasticizers may be used such as phthalate esters,isophthalate esters, terephthalate esters, citric acid esters, fattyacids, fatty acid esters, fatty alcohols, triglycerides, diglycerides,monoglycedrides and any combination thereof. Limitations withconventional plasticizing agents can include the ability to rapidly addand remove them to the polymeric coating via a gas phase.

Lastly, for practically any polymer, a good plasticizer can be themonomer of which that polymer is composed. These are often unsaturatedmolecules, with some potential reactivity, so their removal after theprocess is desirable.

Any of the above agents can be in solid, liquid, gas or vapor form.

In some embodiments, the intent of the invention, for example reductionis glass transition temperature or shore harness can be achieved byexposure, at any of the previously disclosed time periods, of thepolymeric component (e.g., coating on a balloon expandable stent) to aprocess selected from a group consisting of exposure to vapor, exposureto moisture, exposure to a gas, exposure to a plasticizing agent,exposure to a solvent vapor, exposure to polymer monomer vapor, exposureto liquid solvent, exposure to liquid polymer monomer, exposure toplasticizing agent vapor, such that the vapor, gas, agent, solvent, etc.can be selected from anyone of the disclosed material.

The percentage and duration of humidity or the amount of plasticizingagent should be of a level that the material becomes ductile enough toadequately lower the brittleness of the stent or the coating of thestent. Adequate means having a value for the parameter in question suchthat one of ordinary skill in the art would expect the invention tofunction in the particular application. For example, “adequately lowerthe brittleness of the stent” means that the brittleness of the stent isreduced enough to such that the cracking in the stent or coating isreduced or significantly minimized (as compared to when any of theprocedures of the present invention are not followed).

Polymers on crimped stents or crimped polymeric stents exhibit adhesiveand cohesive failure as two main failure modes. In adhesive failure,polymer is sheared off the stent due to poor adhesion to the metal stentor between the polymer molecules in a polymeric stent. This is a failureof the polymer due to poor interaction between polymer molecules and thesubstrate. Since moisture and other plasticizing agents make polymericmaterials softer, the methods of the present invention should assist inpreventing adhesive failure. Adhesive failure is sometimes referred toas an adhesive-based failure or delamination-based failure. When apolymer exhibits adhesive failure, that polymer becomes a candidate forcrimping methods of the present invention. Adhesive failure is alsocaused by a build-up of stress. Moisture and plasticizing agents lowerthe polymer's modulus and decreases the internal stress within thepolymer. When stents are crimped, whether polymer coated orsubstantially polymeric, certain portions of the stent undergoelongation and compression. If too much elongation occurs, the polymerwill crack. The ultimate elongation of polymers depends on a variety offactors, including presence of moisture or plasticizing agent. Theembodiments of the present invention can increase the ultimateelongation, thereby preventing failure. If the polymer exhibits acohesive failure due to insufficient elongation, it is also a candidatefor crimping methods of the present invention.

In some embodiments, the medical devices are to be those adapted forplacement in arterial, venous, neurovascular, urethral, biliary,prostate, intravascular, ureteral, bronchial, esophageal, fallopial,tracheal, laryngeal, gastrointestinal, lymphatic, eustachiaic,pancreatic, cerebral, other genitourinary, other gastrointestinal, orother respiratory lumens or passages.

In some embodiments the methods act on polymeric materials comprisingABS resins; acrylic polymers and acrylic copolymers;acrylonitrile-styrene copolymers; alkyd resins; biomolecules; celluloseethers; celluloses; copoly(ether-esters); copolymers of polycarboxylicacids and poly-hydroxycarboxylic acids; copolymers of vinyl monomerswith each other and olefins; cyanoacrylates; epoxy resins; ethylenevinyl alcohol copolymers; ethylene-methyl methacrylate copolymers;ethylene-vinyl acetate copolymers; ethylene-α-olefin copolymers;poly(amino acids); poly(anhydrides); poly(butyl methacrylates);poly(ester amides); poly(ester-urethanes); poly(ether-urethanes);poly(imino carbonates); poly(orthoesters); poly(silicone-urethanes);poly(tyrosine arylates); poly(tyrosine-derived carbonates);polyacrylates; polyacrylic acid; polyacrylic acids; polyacrylonitrile;polyacrylonitrile; polyalkylene oxalates; polyamides; polyamino acids;polyanhydrides; polycarbonates; polycarboxylic acids;polycyanoacrylates; polyesters; polyethers; poly-hydroxycarboxylicacids; polyimides; polyisobutylene and ethylene-α-olefin copolymers;polyketones; polymethacrylates; polyolefins; polyorthoesters;polyoxymethylenes; polyphosphazenes; polyphosphoesters; polyphosphoesterurethanes; polyphosphoesters; polyphosphoesters-urethane; polyurethanes;polyvinyl aromatics; polyvinyl esters; polyvinyl ethers; polyvinylketones; polyvinylidene halides; silicones; starches; vinyl copolymersvinyl-olefin copolymers; and vinyl halide polymers and copolymers.Specific examples of useful polymers for some embodiments include thefollowing polymers: starch, sodium alginate, rayon-triacetate, rayon,polyvinylidene fluoride, polyvinylidene chloride, polyvinyl pyrrolidone,polyvinyl methyl ether, polyvinyl chloride, polyvinyl acetate,polystyrene, polyisocyanate, polyisobutylene, polyethylene glycol,polydioxanone, polycaprolactone, polycaprolactam, KYNAR (brandpoly(vinylidene fluoride) available from Atofina), polyacrylonitrile,poly(trimethylene carbonate), poly(L-lactic acid),poly(lactide-co-glycolide), poly(hydroxyvalerate),poly(hydroxybutyrate-co-valerate),poly(hydroxybutyrate-co-hydroxyvalerate), poly(hydroxybutyrate),poly(glycolide), poly(glycolic acid), poly(D,L-lactide-co-L-lactide),poly(D,L-lactide-co-glycolide), poly(D,L-lactide),poly(4-hydroxybutyrate), poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), Nylon 66, hyaluronic acid, fibrinogen, fibrin,elastin-collagen, collagen, cellulose propionate, cellulose nitrate,cellulose butyrate, cellulose acetate butyrate, cellulose acetate,cellulose, cellophane, carboxymethyl cellulose, or poly(2-hydroxyethylmethacrylate), Chitin, Chitosan, EVAL, poly(butyl methacrylate),poly(D,L-lactic acid), poly(D,L-lactide), poly(glycolicacid-co-trimethylene carbonate), poly(hydroxybutyrate-co-valerate),poly(hydroxyvalerate), poly(iminocarbonate), poly(lactide-co-glycolide),poly(L-lactic acid), poly(N-acetylglucosamine), poly(trimethylenecarbonate), poly(vinyl chloride), poly(vinyl fluoride), poly(vinylidenechloride), poly(vinylidene fluoride), poly(vinylidenefluoride-co-chlorotrifluoroethylene), poly(vinylidenefluoride-co-hexafluoropropene), polyanhydride, polyorthoester,polyurethane, polyvinyl alcohol, polyvinyl chloride, rayon, SOLEF 21508(formulation available from Solvay Solexis), and PEO/PLA. Someembodiments select the group of polymers to specifically exclude any oneof or any combination of the polymers listed above.

In one embodiment, the methods of the invention are particularly usedfor PC1036 polymer or coating or stent body including this polymer.PC1036 can be used as a mixture with any of the above describedpolymers. PC1036 is a phosphoryl choline acrylate polymer produced byBiocompatibles (based out of the United Kingdom). PC1036 is anall-acrylate backbone, synthetic polymer, which cross-links to form acontiguous coating. PC1036 can be represented as follows:

Scheme IA and IB are cross-linking schemes:

When dry, PC1036 is quite brittle with a Tg of 95° C. However, thepolymer can absorb up to 30% water by weight, and becomes quiteflexible.

The polymeric component for use with this invention can comprise amixture of polymers, such as an intimate mixture of polymer molecules,or can use a combination of polymers arranged in a layered structure.The polymers used can also be chemically bonded or cross-linked.

Some embodiments add conventional drugs, such as small, hydrophobicdrugs. Some embodiments graft-on conventional drugs or mix conventionaldrugs with the polymers. The polymers can serve as base or topcoatlayers for the coating constructs.

The selected drugs can inhibit vascular, smooth muscle cell activity.More specifically, the drug activity can aim at inhibiting abnormal orinappropriate migration or proliferation of smooth muscle cells toprevent, inhibit, reduce, or treat restenosis. The drug can also includeany substance capable of exerting a therapeutic or prophylactic effect.Examples of such active agents include antiproliferative,antineoplastic, antiinflammatory, antiplatelet, anticoagulant,antifibrin, antithrombin, antimitotic, antibiotic, and antioxidantsubstances, as well as their combinations, and any prodrugs,metabolites, analogs, congeners, derivatives, salts and theircombinations.

An example of an antiproliferative substance is actinomycin D, orderivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 WestSaint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available fromMerck). Synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin II, actinomycin X1, and actinomycin C1. Examples ofantineoplastics include paclitaxel and docetaxel. Examples ofantiplatelets, anticoagulants, antifibrins, and antithrombins includeaspirin, sodium heparin, low molecular weight heparin, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogs,dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin),dipyridamole, glycoprotein IIb/IIIa platelet membrane receptorantagonist, recombinant hirudin, thrombin inhibitor (available fromBiogen), and 7E-3B® (an antiplatelet drug from Centocor). Examples ofantimitotic agents include methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, adriamycin, and mutamycin. Examples ofcytostatic or antiproliferative agents include angiopeptin (asomatostatin analog from Ibsen), angiotensin converting enzymeinhibitors such as CAPTOPRIL (available from Squibb), CILAZAPRIL(available from Hoffman-LaRoche), or LISINOPRIL (available from Merck &Co., Whitehouse Station, N.J.), calcium channel blockers (such asNifedipine), colchicine, fibroblast growth factor (FGF) antagonists,histamine antagonist, LOVASTATIN (an inhibitor of HMG-CoA reductase, acholesterol lowering drug from Merck & Co.), monoclonal antibodies (suchas PDGF receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitor (available from Glazo), Seramin (a PDGFantagonist), serotonin blockers, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. Other usefuldrugs may include alpha-interferon, genetically engineered epithelialcells, dexamethasone, estradiol, clobetasol propionate, cisplatin,insulin sensitizers, receptor tyrosine kinase inhibitors, andcarboplatin. Exposure of the composition to the drug should notadversely alter the drug's composition or characteristic. Accordingly,drug containing embodiments choose drugs that are compatible with thecomposition. Rapamycin is a suitable drug. Additionally, methylrapamycin, everolimus, 40-O-(2-hydroxy)ethyl-rapamycin,40-O-tetrazolylrapamycin (ABT-578), or 40-epi-(N1-tetrazolyl)-rapamycinor functional analogs or structural derivatives thereof, is suitable, aswell. Examples of analogs or derivatives of40-O-(2-hydroxy)ethyl-rapamycin include, among others,40-O-(3-hydroxy)propyl-rapamycin and40-O-2-(2-hydroxy)ethoxyethyl-rapamycin. Those of ordinary skill in theart know of various methods and coatings for advantageously controllingthe release rate of drugs, such as 40-O-(2-hydroxy)ethyl-rapamycin.

Examples of implantable devices useful in the present invention includeself-expandable stents, balloon-expandable stents, and stent-grafts. Theunderlying structure of the device can be of virtually any design. Thedevice can comprise a metallic material or an alloy such as, but notlimited to, cobalt chromium alloy (ELGILOY), stainless steel (316L),high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloyL-605, “MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titaniumalloy, platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium, and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. The stent can be made from abioabsorable polymer. Bioabsorbable is intended to includebiodegradable, bioerodable and biodissolvable polymers. Of course, oneof ordinary skill in the art recognizes that the invention is useful formedical devices that use a crimping step in their production.

Any of the above described procedures can be used to reduce a stent indiameter, such as a self-expanding stent, and inserting the stent in asheath to constrain the stent. Once the stent is withdrawn out from thesheath, the stent expands to a larger diameter.

Various, specialized tests are used to assay the integrity of a drugdelivery stent coating. In all of them, completed units are tested whichhave been though all stent-catheter assembly processes, includingcrimping processes. One test is inspection of the coated stents byscanning electron microscopy. This can be done on the completed units bycutting the stent-balloon section from the catheter, or the stent can beremoved from the catheter by dry expansion in air or wet expansion inaqueous solution. Under SEM, the fraction of compromised coating surfacearea can be estimated. Compromised coating is coating that has beencracked, deformed, torn, or removed. When this fraction of surface areaexceeds 5-10%, the drug-release-rate properties, and total drug contentcan be affected. Another measure of coating integrity, which is tied tocrimping damage, is the number and size of particles shed when the stentis expanded in aqueous solution. The stent is deployed in a solution ofpreviously filtered water and the particles shed are counted by one ofseveral available particle-counting instruments. Example instrumentswould be those that work by light scattering, instruments that work bylight obscuration, such as the Hiac-Royco, or the Coulter counter whichworks by electrical conductivity. Elevated numbers, and sizes, ofparticles shed are indicative of coating failure, which is affected bycrimping damage either in the form of coating pieces that are completelyshorn off, or cracks in the coating which propagated during stentexpansion to liberate particles. Yet another approach to measuring theeffects of coating crimping damage is by acute thrombogenicity testing,one example of which is that detailed by Sukavaneshvar et al. ASAIOJournal, Aug. 11, 2000, p 301 and ASIAO Journal, Jul. 5, 2000, p M393,which approach subjected stents deployed in tubing to a flow of bovineblood in which the platelets have been radiolabeled. Accumulation ofplatelets and thrombus is a measure of the acute thrombogenicity. Theeffect of coating cracks and defect can be compared to uncoated stents,or to stents where the coatings have fewer, or no cracks and coatingdefects.

While particular embodiments of the invention have been shown anddescribed, it will be obvious to those skilled in the art that changesand modifications can be made without departing from this invention inits broader aspects and, therefore, the appended claims are to encompasswithin their scope all such changes and modifications as fall within thetrue spirit and scope of the invention.

What is claimed is:
 1. A method of producing a stent-balloon assembly,comprising: crimping, with a crimping apparatus, a stent on a balloon ofa catheter assembly, wherein (i) the stent is a metallic stent; (ii) thestent has a coating including a phosphoryl choline acrylate polymer anda drug; and (iii) the crimping is conducted in an environment having arelative humidity of 30% to 80%.
 2. The method of claim 1, wherein theduration of exposure to humidity is long enough for absorption ofmoisture so as to lower the glass transition temperature or shorehardness of the coating during the crimping process.
 3. The method ofclaim 1, wherein the humidity level of 30% to 80% is maintained untilthe stent is considered crimped and compressed on the balloon by thecrimping apparatus.
 4. The method of claim 1, wherein exposure to thehumidity level of 30% to 80% continues after the disengagement of thecrimping apparatus from the stent.
 5. The method of claim 1, wherein thecrimping is conducted in a closed humidity chamber.
 6. The method ofclaim 1, wherein the crimping is conducted at a temperature greater than25 deg. C.
 7. The method of claim 1, wherein the drug is a rapamycinderivative.
 8. The method of claim 1, wherein the crimping is conductedin an environment having a relative humidity of 40% to 70%.
 9. Themethod of claim 1, wherein the crimping is conducted in an environmenthaving a relative humidity of 45% to 55%.
 10. The method of claim 1,wherein the crimping is conducted in an environment having a relativehumidity of 55% to 60%.
 11. The method of claim 1, wherein the crimpingis conducted in an environment having a relative humidity of 55% to 60%,and wherein the drug is a rapamycin derivative.
 12. The method of claim11, wherein exposure to the humidity level continues after thedisengagement of the crimping apparatus from the stent.
 13. The methodof claim 11, wherein the humidity level is maintained until the stent isconsidered crimped and compressed on the balloon by the crimpingapparatus.
 14. A method of producing a stent-balloon assembly,comprising: crimping, with a crimping apparatus, a stent on a balloon ofa catheter assembly, wherein (i) the stent is a metallic stent; (ii) thestent has a coating including a phosphoryl choline acrylate polymer anda drug; and (iii) the crimping is conducted in an environment having arelative humidity of 30% to 80%, wherein the phosphoryl choline acrylatepolymer is PC1036 polymer of the following formula:


15. The method of claim 14, wherein the crimping is conducted in anenvironment having a relative humidity of 55% to 60%.
 16. The method ofclaim 14, wherein the crimping is conducted in an environment having arelative humidity of 55% to 60%, and wherein the drug is a rapamycinderivative.
 17. The method of claim 16, wherein exposure to the humiditylevel continues after the disengagement of the crimping apparatus fromthe stent.
 18. The method of claim 16, wherein the humidity level ismaintained until the stent is considered crimped and compressed on theballoon by the crimping apparatus.